Expanded Answers for Study Problems in: Rowland & Tozer's Clinical Pharmacokinetics: Concepts and Applications, 3rd edition.

Chapter 12 - Integration with Kinetics

Study Problems on Page 197-199

2. You'll note that in Table 12-6 for each line there is only one column with an increase, the rest have no change. This denotes that only the parameter with an increase is changing, the other parameters remain unchanged. An explanation for the column in each line is provided below:

Line 1 This is essentially asks what happens to a drug with a high hepatic extraction ratio when hepatic blood flow increases, but plasma protein and tissue binding (expressed as fraction in blood unbound and fraction in tissue unbound) remain constant? Since for a drug with a high E,

CL_H ~ Q_H ,

an increase in Q_H will result in an increase in the Total Clearance. On the other hand, volume of distribution remains unchanged since blood volume, tissue volume, blood and tissue binding do not change. Since

t_1/2 = 0.693Vd/CL ,

an increase in CL while Vd remains constant will result in a decrease in t_1/2. The effect of an increase in Q_H on oral bioavailability depends on how what parameter is used to assess oral bioavailability. If oral bioavailability is determined by F, where

F = Q_H/(Q_H + f_ubCL_uint),

then increasing Q_H will increase oral bioavailability. However, oral bioavailability is usually estimated by AUC_o, where

AUC_o = Do/(f_ubCL_uint)

Using AUC_o to estimate oral bioavailability, it is readily seen that this parameter is independent of hepatic blood and would, therefore, not change.

Line 2 What happens to a high extraction drug when blood flow and tissue binding are held constant, but f_ub is decreased? Since the CL_H is dependent upon blood flow, changes in plasma protein binding will not affect the total clearance. However, since

V_ss = V_b + V_t(f_ub/f_ut)

a decrease in plasma protein binding will decrease the volume of distribution. A decrease in volume of distribution in the presence of no change in total clearance will result in a decrease in half-life. The oral bioavailability, measured as either F or AUC_o (see answer for Line 1), will increase with a decrease in the fraction in blood unbound.

Line 3 What happens to a high extraction drug when blood flow and blood binding are held constant, but f_ut is increased (i.e., tissue binding is decreased)? From the equations provided in the answer to Line 1, it is clear that total clearance and oral bioavailability are independent of tissue binding, so neither parameter will change. As shown in the equation for V_ss above, an increase in the fraction unbound in tissue will result in a decrease in volume of distribution; which, in turn, results in a decrease in half-life.

Line 4 What happens to a low extraction drug when blood flow is increased and binding remains unchanged? Since for a low extraction drug

CL_H ~ f_ubCL_uint

changing blood flow will not influence total clearance. As it also has no effect in volume of distribution, none of the parameters are changed for a low extraction drug when blood flow is increased.

Line 5 What occurs when the fraction in tissue unbound increases for a low extraction drug? While clearance is independent of tissue binding, volume of distribution will decrease with an increase in the fraction in tissue unbound (see equation in answer for Line 2). The decrease in volume of distribution, in the face of an unchanged total clearance, will result in a decrease in the half-life of the compound.

Line 6 What occurs for a low extraction drug when hepatic blood flow is held constant while fraction in blood and tissue unbound both increase? The answer in the book assumes that blood and tissue binding change proportionately. As shown in the equation in he answer for Line 4, and increase in the unbound drug in blood will cause an increase in the total clearance. If the fraction in blood unbound changes proportionately to the change in fraction in tissue unbound, these two changes will offset and no change will be seen in the volume of distribution. The increased clearance in the face of no change in volume of distribution will result in a decrease in the half-life. For a low extraction drug

f_ubCL_uint <<Q_H

.

This indicates that F will not change as the fraction in blood unbound increases. However, AUC_o will decrease with an increase in the fraction in blood unbound (f_ub)[see equation in answer for Line 1].

4. Quite clearly, the predominant site of interaction is a marked reduction in the first-pass effect when allopurinol is given with 6-mercaptopurine. The systemic clearance is not altered significantly because the drug is a high clearance agent whose hepatic clearance is essentially equivalent to hepatic blood flow. This interaction demonstrates the fact the metabolic drug interaction may be dependent on the route of administration of the effected agent. The observation is predicted by the models of hepatic drug clearance discussed.

Return to Pharmacokinetics and Biopharmaceutics Homepage

Return to Expanded Answers for Study Problems Index Page